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Binding of HMG-I(Y) elicits structural changes in a silencer of the human beta-globin gene.

Abstract
Proteins involved in repression of the human beta-globin gene may be useful in the treatment of sickle cell anemia, in conjunction with therapy to reactivate fetal globin genes. If there is a reciprocal elevation of gamma-globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the beta-globin gene appears to be mediated through two DNA sequences, silencers I and II, and identified a protein termed BP1 which binds to both silencer sequences. In this study, we cloned two cDNAs encoding proteins which bind to an oligonucleotide in silencer I containing a BP1 binding site. These cDNAs correspond to HMG-I and HMG-Y, isoforms regarded as architectural proteins. We demonstrate that binding of HMG-I(Y) to this oligonucleotide causes bending/flexure of the DNA. HMG-I(Y) also binds to a second oligonucleotide containing a BP1 binding site located in a negative control region upstream of the delta-globin gene, suggesting a role for HMG-I(Y) in repression of adult globin genes. Expression studies revealed that HMG-I(Y) is ubiquitously expressed in human tissues that do not express beta-globin, being present in 48 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG-I(Y) expression is down-regulated during differentiation of primary erythroid cells. We present a model in which HMG-I(Y) alters DNA conformation to allow binding of repressor proteins, and in which the relative amount of HMG-I(Y) helps to determine the repressive state of the beta-globin gene.
AuthorsM B Chase, S B Haga, W D Hankins, D M Williams, Z Bi, J W Strovel, C Obriecht, P E Berg
JournalAmerican journal of hematology (Am J Hematol) Vol. 60 Issue 1 Pg. 27-35 (Jan 1999) ISSN: 0361-8609 [Print] United States
PMID9883803 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • RNA, Messenger
  • Transcription Factors
  • HMGA1a Protein
  • Globins
Topics
  • Blotting, Northern
  • Cell Differentiation (physiology)
  • DNA-Binding Proteins (genetics)
  • Erythrocytes (cytology)
  • Globins (genetics, metabolism)
  • HMGA1a Protein
  • High Mobility Group Proteins (genetics, metabolism)
  • Humans
  • RNA, Messenger (metabolism)
  • Tissue Distribution
  • Transcription Factors (genetics, metabolism)
  • Transcription, Genetic (genetics)

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